Urea cycle disorders (UCD) are inborn errors of metabolism caused by a deficiency in one of six enzymes or two mitochondrial transport proteins involved in the production of urea, resulting in accumulation of toxic levels of ammonia in the blood (hyperammonemia). UCD subtypes include those caused by an X-linked mutation and corresponding deficiency in ornithine transcarbamylase (OTC) and those caused by autosomal recessive mutations with corresponding deficiencies in argininosuccinate synthetase (ASS), carbamyl phosphate synthetase (CPS), argininosuccinate lyase (ASL), arginase (ARG), N-acetylglutamate synthetase (NAGS), ornithine translocase (HHH), and aspartate glutamate transporter (CITRIN). These are rare diseases, with an overall estimated incidence in the United States of approximately 1 in every 35,000 live births. UCD is suspected when a subject experiences a hyperammonemic event with an ammonia level >100 μmol/L accompanied by signs and symptoms compatible with hyperammonemia in the absence of other obvious causes and generally confirmed by genetic testing.
The severity and timing of UCD presentation vary according to the severity of the deficiency, which may range from minor to extreme depending on the specific enzyme or transporter deficiency, and the specific mutation in the relevant gene. UCD patients may present in the early neonatal period with a catastrophic illness, or at any point in childhood, or even adulthood, after a precipitating event such as infection, trauma, surgery, pregnancy/delivery, or change in diet. Acute hyperammonemic episodes at any age carry the risk of encephalopathy and resulting neurologic damage, sometimes fatal, but even chronic, sub-critical hyperammonemia can result in impaired cognition. UCDs are therefore associated with a significant incidence of neurological abnormalities and intellectual and developmental disabilities over all ages. UCD patients with neonatal-onset disease are especially likely to suffer cognitive impairment and death compared with patients who present later in life.
Management of acute hyperammonemic crises may require hemodialysis and/or intravenous (IV) administration of sodium phenylacetate (NaPAA) and sodium benzoate (NaBz) (the admixture is marketed in the U.S. as AMMONUL®). Orthotopic liver transplantation may also be considered for patients with severe disease that manifests itself in the neonatal period. Long-term UCD management is directed toward prevention of hyperammonemia and includes restriction of dietary protein; arginine and citrulline supplementation, which can enhance waste nitrogen excretion for certain UCDs; and oral, ammonia-scavenging drug therapy that provides an alternate path for waste nitrogen removal (RAVICTI® (glycerol phenylbutyrate, GPB) Oral Liquid or sodium phenylbutyrate (NaPBA; marketed in the U.S. as BUPHENYL® and in the European Union (EU) as AMMONAPS®)).
RAVICTI®, formerly HPN-100, a prodrug of PBA and a pre-prodrug of the active compound phenylacetate (PAA), has been approved in the U.S. for use as a nitrogen-binding agent for chronic management of adult and pediatric patients ≥2 years of age with UCDs who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. RAVICTI® is glycerol phenylbutyrate, a triglyceride containing 3 molecules of PBA linked to a glycerol backbone, the chemical name of which is benzenebutanoic acid, 1′,1″-(1,2,3-propanetriyl) ester.
Glycerol phenylbutyrate is used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements). RAVICTI® is not indicated for the treatment of acute hyperammonemia in patients with UCDs, and the safety and efficacy of RAVICTI® for the treatment of NAGS deficiency has not been established. The RAVICTI® Package Insert states the drug is contraindicated in patients less than 2 months of age, stating that children less than 2 months of age may have immature pancreatic exocrine function, which could impair hydrolysis of RAVICTI®, leading to impaired absorption of phenylbutyrate and hyperammonemia; and in patients with known hypersensitivity to phenylbutyrate (signs include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash).
While the U.S. approval of RAVICTI® was based on its evaluation in 6 clinical trials involving over 100 adult and pediatric UCD patients aged 2 months old and above, only 7 patients aged 2 months to 2 years were enrolled in these studies. Among the 4 patients aged 2 months to 2 years who participated in an open label, fixed-sequence switch-over comparison of RAVICTI® to NaPBA, mean ammonia exposure assessed at 24-hour area under the curve was non-inferior on RAVICTI®. PAA exposure, also assessed as 24-hour area under the curve, was very similar. However, the number of patients in this age group studied at the time of RAVICTI's approval was small and considerable patient-to-patient variability was observed.
Children less than 2 months of age may have immature pancreatic exocrine function, which could impair hydrolysis of glycerol phenylbutyrate leading to impaired absorption of PBA and potentially hyperammonemia. While the limited data available suggest that pancreatic enzymes present in newborns include pancreatic lipase-related protein and bile salt-stimulated lipase (which digest triglycerides present in human breast milk), both of which hydrolyze glycerol phenylbutyrate in vitro, it is not known whether pancreatic function in newborns is sufficiently mature to digest glycerol phenylbutyrate. In addition, the metabolism of PAA is known to vary with body size, and given that body size changes dramatically during the first two years of life, there has been significant uncertainty how glycerol phenylbutyrate or NaPBA could be used in these patient populations from birth to two years of age.
Dosing of UCD patients less than 2 years of age is particularly difficult. In contrast to patients detected based on The Newborn Screen who may be mildly affected, patients less than 2 years of age presumably have little to no endogenous urea cycle activity. That is, patients less than 2 years of age presenting in crisis presumably have little or no ‘innate’ ability to convert ammonia to urea, such that they may be totally dependent on the drug to rid the body of waste nitrogen (including ammonia) via the alternate pathway. Thus there is little to no room for error since there is no endogenous capacity to buffer drug ‘underdosing’. Patients less than 2 years of age are also particularly susceptible to overdosing because of their slower clearance of PAA.
There is a significant, unmet need for a nitrogen scavenging drug that can be used in UCD patients less than 2 years of age. Further, for the purposes of dose monitoring, frequent blood draws are difficult in neonates and children under two years of age and a non-invasive measure is needed. The present disclosure meets these needs.